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Adipose tissue insulin resistance predicts the incidence of hypertension: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases

A Comment to this article was published on 13 September 2022

Abstract

We investigated the association of adipose tissue insulin resistance with blood pressure and hypertension incidence, comparing it with hepatic and skeletal muscle insulin resistance. The cross-sectional analysis included 6892 general health checkup examinees (mean age: 69.3 years; 51.3% women and 48.7% men) who had no cardiovascular disease. Of those, 3948 normotensive participants (mean age: 68.4 years; 54.8% women and 45.2% men) were enrolled in the retrospective cohort analysis. The adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and free fatty acid levels. A high adipo-IR, high homeostasis model assessment of insulin resistance (HOMA-IR), and low Matsuda index were indicated based on the optimal cutoff values in a receiver operating characteristic curve analysis. Adipo-IR (β = 0.096, P < 0.001), HOMA-IR (β = 0.052, P < 0.001), and Matsuda index (β = −0.055, P < 0.001) were associated with systolic blood pressure in the cross-sectional analysis. Over a mean 5.3-year follow-up period, 1310 participants developed hypertension. A high adipo-IR (adjusted OR, 1.29; 95% CI, 1.11–1.51), but not HOMA-IR or Matsuda index, was significantly associated with the incidence of hypertension. Moreover, the combination of high adipo-IR with high HOMA-IR or low Matsuda index showed no higher odds of hypertension than a high adipo-IR alone. These results suggest that insulin resistance is associated with blood pressure control regardless of the tissue in which it occurs; however, the risk of hypertension is determined by insulin resistance in adipose tissue rather than in liver or muscle tissue.

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References

  1. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al. Insulin resistance in essential hypertension. N. Engl J Med. 1987;317:350–7.

    Article  CAS  PubMed  Google Scholar 

  2. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities-the role of insulin resistance and the sympathoadrenal system. N. Engl J Med. 1996;334:374–81.

    Article  CAS  PubMed  Google Scholar 

  3. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98:2133–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nielsen S, Guo Z, Albu JB, Klein S, O’Brien PC, Jensen MD. Energy expenditure, sex, and endogenous fuel availability in humans. J Clin Invest. 2003;111:981–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Engeli S, Gorzelniak K, Kreutz R, Runkel N, Distler A, Sharma AM. Co-expression of renin-angiotensin system genes in human adipose tissue. J Hypertens. 1999;17:555–60.

    Article  CAS  PubMed  Google Scholar 

  6. Huby AC, Antonova G, Groenendyk J, Gomez-Sanchez CE, Bollag WB, Filosa JA, et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 2015;132:2134–45.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang L, Curhan GC, Forman JP. Plasma resistin levels associate with risk for hypertension among nondiabetic women. J Am Soc Nephrol. 2010;21:1185–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Koenen M, Hill MA, Cohen P, Sowers JR. Obesity, adipose tissue and vascular dysfunction. Circ Res. 2021;128:951–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Levin G, Kestenbaum B, Ida Chen YD, Jacobs DR Jr, Psaty BM, Rotter JI, et al. Glucose, insulin, and incident hypertension in the multi-ethnic study of atherosclerosis. Am J Epidemiol. 2010;172:1144–54.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sung KC, Lim S, Rosenson RS. Hyperinsulinemia and homeostasis model assessment of insulin resistance as predictors of hypertension: a 5-year follow-up study of Korean sample. Am J Hypertens. 2011;24:1041–5.

    Article  PubMed  Google Scholar 

  11. Arshi B, Tohidi M, Derakhshan A, Asgari S, Azizi F, Hadaegh F. Sex-specific relations between fasting insulin, insulin resistance and incident hypertension: 8.9 years follow-up in a Middle-Eastern population. J Hum Hypertens. 2015;29:260–7.

    Article  CAS  PubMed  Google Scholar 

  12. Furugen M, Saitoh S, Ohnishi H, Akasaka H, Mitsumata K, Chiba M, et al. Matsuda-DeFronzo insulin sensitivity index is a better predictor than HOMA-IR of hypertension in Japanese: the Tanno-Sobetsu study. J Hum Hypertens. 2012;26:325–33.

    Article  CAS  PubMed  Google Scholar 

  13. Kaze AD, Musani SK, Correa A, Bertoni AG, Golden SH, Abdalla M, et al. Insulin resistance, metabolic syndrome, and blood pressure progression among Blacks: the Jackson Heart Study. J Hypertens. 2021;39:2200–9.

    Article  CAS  PubMed  Google Scholar 

  14. Goff DC Jr, Zaccaro DJ, Haffner SM, Saad MF. Insulin Resistance Atherosclerosis Study. Insulin sensitivity and the risk of incident hypertension: insights from the Insulin Resistance Atherosclerosis Study. Diabetes Care. 2003;26:805–9.

    Article  PubMed  Google Scholar 

  15. Arnlöv J, Pencina MJ, Nam BH, Meigs JB, Fox CS, Levy D, et al. Relations of insulin sensitivity to longitudinal blood pressure tracking: variations with baseline age, body mass index, and blood pressure. Circulation 2005;112:1719–27.

    Article  PubMed  Google Scholar 

  16. Lai TS, Curhan GC, Forman JP. Insulin resistance and risk of incident hypertension among men. J Clin Hypertens. 2009;11:483–90.

    Article  CAS  Google Scholar 

  17. Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care. 2007;30:89–94.

    Article  CAS  PubMed  Google Scholar 

  18. Søndergaard E, Espinosa De Ycaza AE, Morgan-Bathke M, Jensen MD. How to measure adipose tissue insulin sensitivity. J Clin Endocrinol Metab. 2017;102:1193–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gastaldelli A, Gaggini M, DeFronzo RA. Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the San Antonio Metabolism Study. Diabetes 2017;66:815–22.

    Article  PubMed  Google Scholar 

  20. Hagman E, Besor O, Hershkop K, Santoro N, Pierpont B, Mata M, et al. Relation of the degree of obesity in childhood to adipose tissue insulin resistance. Acta Diabetol. 2019;56:219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim JY, Bacha F, Tfayli H, Michaliszyn SF, Yousuf S, Arslanian S. Adipose tissue insulin resistance in youth on the spectrum from normal weight to obese and from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. Diabetes Care. 2019;42:265–72.

    Article  CAS  PubMed  Google Scholar 

  22. Sasaki N, Maeda R, Ozono R, Nakano Y, Higashi Y. Association of obesity with serum free fatty acid levels in individuals at different stages of prediabetes. Clin Obes. 2022;12:e12496. https://doi.org/10.1111/cob.12496.

    Article  PubMed  Google Scholar 

  23. Sasaki N, Ozono R, Maeda R, Higashi Y. Risk of hypertension in middle-aged and elderly participants with newly diagnosed type 2 diabetes and prediabetes. BMJ Open Diabetes Res Care. 2020;8:e001500. https://doi.org/10.1136/bmjdrc-2020-001500.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sasaki N, Maeda R, Ozono R, Nakano Y, Higashi Y. Common carotid artery flow parameters predict the incidence of hypertension. Hypertension. 2021;78:1711–8.

    Article  CAS  PubMed  Google Scholar 

  25. Sasaki N, Ozono R, Higashi Y, Maeda R, Kihara Y. Association of insulin resistance, plasma glucose level, and serum insulin level with hypertension in a population with different stages of impaired glucose metabolism. J Am Heart Assoc. 2020;9:e015546. https://doi.org/10.1161/JAHA.119.015546.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481.

    Article  PubMed  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9.

    Article  CAS  PubMed  Google Scholar 

  28. DeFronzo RA, Matsuda M. Reduced time points to calculate the composite index. Diabetes Care. 2010;33:e93. https://doi.org/10.2337/dc10-0646.

    Article  PubMed  Google Scholar 

  29. Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. Diagnostic criteria for dyslipidemia. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version. J Atheroscler Thromb. 2013;20:655–60.

    Article  PubMed  Google Scholar 

  30. American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44:S15–S33.

    Article  Google Scholar 

  31. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005;54:1640–8.

    Article  CAS  PubMed  Google Scholar 

  32. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl J Med. 2014;371:1131–41.

    Article  PubMed  Google Scholar 

  33. DeFronzo RA. The effect of insulin on renal sodium metabolism. A review with clinical implications. Diabetologia 1981;21:165–71.

    Article  CAS  PubMed  Google Scholar 

  34. Nickenig G, Röling J, Strehlow K, Schnabel P, Böhm M. Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms. Circulation 1998;98:2453–60.

    Article  CAS  PubMed  Google Scholar 

  35. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87:2246–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Karaca Ü, Schram MT, Houben AJ, Muris DM, Stehouwer CD. Microvascular dysfunction as a link between obesity, insulin resistance and hypertension. Diabetes Res Clin Pr. 2014;103:382–7.

    Article  CAS  Google Scholar 

  37. da Silva AA, do Carmo JM, Li X, Wang Z, Mouton AJ, Hall JE. Role of hyperinsulinemia and insulin resistance in hypertension: metabolic syndrome revisited. Can J Cardiol. 2020;36:671–82.

    Article  PubMed  Google Scholar 

  38. Hall JE, Coleman TG, Mizelle HL, Smith MJ Jr. Chronic hyperinsulinemia and blood pressure regulation. Am J Physiol. 1990;258:F722–731.

    CAS  PubMed  Google Scholar 

  39. Lim K, Burke SL, Head GA. Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits. Hypertension 2013;61:628–34.

    Article  CAS  PubMed  Google Scholar 

  40. Carlsson M, Wessman Y, Almgren P, Groop L. High levels of nonesterified fatty acids are associated with increased familial risk of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2000;20:1588–94.

    Article  CAS  PubMed  Google Scholar 

  41. Fagot-Campagna A, Balkau B, Simon D, Warnet JM, Claude JR, Ducimetière P, et al. High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol. 1998;27:808–13.

    Article  CAS  PubMed  Google Scholar 

  42. Yilmaz MI, Sonmez A, Caglar K, Celik T, Yenicesu M, Eyileten T, et al. Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome. Nephrology. 2007;12:147–53.

    Article  CAS  PubMed  Google Scholar 

  43. Imatoh T, Miyazaki M, Momose Y, Tanihara S, Une H. Adiponectin levels associated with the development of hypertension: a prospective study. Hypertens Res. 2008;31:229–33.

    Article  CAS  PubMed  Google Scholar 

  44. Haynes WG. Interaction between leptin and sympathetic nervous system in hypertension. Curr Hypertens Rep. 2000;2:311–8.

    Article  CAS  PubMed  Google Scholar 

  45. Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell 2014;159:1404–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang J, Thornton JC, Russell M, Burastero S, Heymsfield S, Pierson RN Jr. Asians have lower body mass index (BMI) but higher percent body fat than do whites: comparisons of anthropometric measurements. Am J Clin Nutr. 1994;60:23–28.

    Article  CAS  PubMed  Google Scholar 

  47. Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, De Gregorio M, et al. Racial differences in the relation between blood pressure and insulin resistance. N. Engl J Med. 1991;324:733–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Naomi Yuzono for technical and secretarial assistance. This study did not receive any financial support.

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Correspondence to Nobuo Sasaki.

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Sasaki, N., Maeda, R., Ozono, R. et al. Adipose tissue insulin resistance predicts the incidence of hypertension: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases. Hypertens Res 45, 1763–1771 (2022). https://doi.org/10.1038/s41440-022-00987-0

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